Efficacy of Repeat Immunoadsorption in Post-COVID ME/CFS Patients with Elevated B2-Adrenergic Receptor Autoantibodies - 2024, Stein, Scheibenbogen

[Kalliope]

Preprint
Link to published paper here
**


The Lancet: Efficacy of Repeat Immunoadsorption in Post-COVID ME/CFS Patients with Elevated B2-Adrenergic Receptor Autoantibodies: A Prospective Cohort Study

Abstract
Background: Since the pandemic, SARS-CoV-2 has become the leading trigger for ME/CFS. Evidence indicates autoimmunity plays an important pathophysiological role.

Methods: This prospective cohort study included 20 post-COVID ME/CFS patients found to have elevated β2 AR-AB between October 2022 and October 2023. They received five immunoadsorption sessions at the Charité Universitätsmedizin Berlin, Germany. Response was defined as ≥ ten-point increase in the SF-36 PF four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven out of 14 patients who worsened after initial response received a second cycle.

Findings: The treatment was generally well tolerated, reducing total IgG by 79·15 % (IQR: 75·47 – 83·19%) and β2 AR-AB by 78·14 % (IQR: 67·06 – 86·18%). 14 out of 20 patients responded to the treatment with an increase in the median SF-36 PF score from 25 to 60. Improvements were reported in fatigue (p = 0·028), post-exertional malaise (p = 0·005), pain (p = 0·007), cognitive (p = 0·010), autonomic (p = 0·004), and immunological (p = 0·001) symptoms. Female patients had increased handgrip strength (p = 0·036). In most patients symptoms worsened again after six months.

Interpretation: Immunoadsorption can temporarily improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition’s pathophysiology.


https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4911576

 

[Kalliope]

Scheibenbogen on Twitter:

Our Charité study on immunoadsorption in post-COVID MECFS as a preprint in Lancet: 14 out of 20 improved, but mostly not long-lasting. We are preparing studies on the combination of immunoadsorption with B cell depletion.

https://twitter.com/user/status/1819120514063126550

 

[Hutan]

We are preparing studies on the combination of immunoadsorption with B cell depletion.

Please can they blind these future studies?

Two thirds of patients improving from 25 to 60 on the SF-36 PF score over 6 months in a small unblinded study is interesting, but still within the bounds of a placebo response.

 

[Hutan]

This study was being conducted within the National Clinical Studies Group (NKSG), a clinical
trial and translational research platform focused on developing therapies for PCS and ME/CFS, funded
by the German Ministry of Education and Research (BMBF).21

Five sessions of IA were administered at the Department of Nephrology at Charité-Universitätsmedizin
Berlin. IA treatment was conducted in an outpatient setting over a ten-day period, with sessions spaced
no more than two days apart. The TheraSorb® – Ig omni 5 adsorber (Miltenyi Biotech B.V. & Co. KG, Bergisch Gladbach, Germany) was used for removal of human lambda and kappa chains containing immunoglobulins IgG (subclasses IgG1-IgG4), IgA, IgM, IgE, and immune complexes as well as free lambda and kappa light chains from the plasma.

Patients’ health-related quality of life was assessed using
the 36-Item Short-Form Survey (SF-36), with scores ranging from 0 to 100, with 100 indicating no limitations.26 Response to IA treatment was defined as a minimum increase in the SF-36 physical functioning domain (SF-36 PF) of 10 points at four weeks post IA, indicating a clinically relevant improvement.27

They don't say that SF-36 was the primary outcome. A lot (really a lot) of other things were measured too, e.g. Fatigue Severity Scale, Bell score, PEM-DSQ.
It's looking as though the assessment point was actually 4 weeks after treatment. An assessment period that short is especially prone to bias in an unblinded study.

Also, the 20 participants were noted to want to undergo the treatment - they were selected out of a larger group. The median disease duration was only 22 months, which I guess is unavoidable with the post-Covid selection. And the 20 participants were characterised as having severe disability (usually housebound).

 

[Hutan]

Figure 1: a is the responders, b is the non-responders. SF-36 PF

 

[Hutan]

The improvement in the degree of disability according to the Bell score at four weeks post IA among the responders did not reach statistical significance (z = 1·61, p = 0·107, r = 0·46).

 

[Murph]

it's not the sort of ultra cure you might hope for when matching a treatment to a defined subset. And with people whose course of illness is short, you'd expect some spontaneous remissions. Definitely ambiguous to me whether they have something there.

 

[Simon M]

Please can they blind these future studies?

Two thirds of patients improving from 25 to 60 on the SF-36 PF score over 6 months in a small unblinded study is interesting, but still within the bounds of a placebo response.

Thanks for all the great analysis (as usual).

And yes, I think the Rituximab open label study showed at least as big an effect, while the blinded follow-up showed none.

This study is similarly unblinded with no control, only this time with very short duration where significant improvement might be expected. A full blinded, controlled study would be interesting.

 

[V.R.T.]

I'm endlessly frustrated by studies like these! Is the idea just to get funding for a double-blind study

Because it would be really valuble to know if this stuff actually worked.

 

[Kitty]

Is the idea just to get funding for a double-blind study

Or is it to make money selling their treatment to desperate people.

 

[SNT Gatchaman]

Now published as —

Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study
Elisa Stein; Cornelia Heindrich; Kirsten Wittke; Claudia Kedor; Rebekka Rust; Helma Freitag; Franziska Sotzny; Anne Krüger; Markus Tölle; Patricia Grabowski; Carmen Scheibenbogen; Laura Kim

BACKGROUND
Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.

METHODS
This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023.

PATIENTS
with a median disease duration of 22 months (IQR: 15–31), were treated with five immunoadsorption sessions at Charite -Universitatsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36–51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.

FINDINGS
The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73–84%) and β2 AR-AB by 77% (CI: 58–95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41–26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.

INTERPRETATION
Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition's pathophysiology.

FUNDING
Funded by The Federal Ministry of Education and Research and the Weidenhammer Zobele Research Foundation.


Link | PDF (The Lancet Regional Health – Europe)

 

[Yann04]

Note that this study didn’t have a control group and therefore had no bliding. And most of the participants had only been sick 1-3 years (median 22 months) which is a timeframe which often coincides with natural improvements.

Also, if later on we do learn that this treatment does in fact work, I would guess it’s possible it only works in the early stage of the disease before the condition becomes “permanent”.

 

[Dolphin]

ME Research UK:

Researchers at Charité University Hospital in Berlin highlighted evidence that autoantibodies may be involved in the pathophysiology (underlying disease processes) of long COVID and ME/CFS. To test the hypothesis, they recruited 20 individuals with long COVID, who met the Canadian Consensus Criteria for ME/CFS, for immunoadsorption treatment to remove certain autoantibodies. The majority of patients experienced a clinical improvement in symptoms at six months.

The team is currently conducting randomised controlled trials with larger sample sizes to better assess the effectiveness of immunoadsorption in post-COVID ME/CFS.

Read more: https://bit.ly/3DJIcGp